Project Summary: Sigma-1 receptor (Sigmar1) is a molecular chaperone that is widely expressed in the heart. We showed that Sigmar1 expression is significantly decreased in both human heart failure and in a protein conformation disorder that occurs as a result of cardiomyocyte-specific expression of mutant -B-crystallin (CryABR120G). Despite having potential cardioprotective functions, Sigmar1's role in the heart remains obscure and little is known about Sigmar1's subcellular distribution, functionality, role in heart disease and its downstream signaling effects in the cardiac compartment. To address these limitations, I will use cardiomyocyte-specific Sigmar1 transgenic (Tg) mice and global knockout mice to explore the functionality of Sigmar1 in the heart. The overall objective of this proposal is to uncover the novel molecular functions and mechanisms of Sigmar1 in order to protect the myocardium from both external stimuli and intrinsic insults. Two models of injury will be used: ischemia/reperfusion injury and protein conformation disorder-induced cardiomyopathy. Using both gain-of-function and loss-of-function approaches, I will establish a direct cause-effect relationship to define the involvement and potential protective role of Sigmar1 under pathophysiological conditions in the heart. The central hypothesis is that Sigmar1 activation can be cardioprotective, preventing pathological cardiac remodeling by regulating Ca2+ influx from ER into mitochondria and acting as a chaperone to degrade misfolded proteins. Guided by strong preliminary data, this hypothesis will be tested by pursuing 3 specific aims: 1) To determine the functional role of Sigmar1 in the heart at baseline and in response to heart failure-inducing stimuli. 2) To test the hypothesis that activation of Sigmar1 is sufficient to protect the heart against protein conformation disorder-induced adverse remodeling and heart failure. 3) To determine if the molecular mechanism underlying Sigmar1- dependent cardioprotection depends upon regulating the calcium influx from ER into mitochondria. These studies will uncover new mechanistic perspectives to therapeutically approach heart failure and will also provide candidates for pharmacologic and genetic targeting.